This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project focuses on understanding the reasons why natural hosts for Simian Immunodeficiency Virus infection, such the African monkey species sooty mangabeys, in striking contrast to what happens in HIV-infected individuals, are not susceptible to AIDS despite being infected with a virus that replicates continuously and at very high levels. As shown below in the list of publications, in the past year the work supported by this grant has allowed us to discover that, in SIV-infected sooty mangabeys: (i) upregulation of the inhibitory molecule PD-1 is associated with decline of immune activation in lymph nodes;(ii) availability of target CD4+ T cells is the key determinant of the level of virus replication;(iii) preservation of normal levels of mucosal T helper 17 CD4+ T cells is instrumental to maintaining mucosal integrity and lack of microbial translocation. A better definition of the mechanisms underlying this phenotype may provide clues to understanding the reasons why humans infected with HIV develop AIDS. We are hopeful this data will pave the way to new therapies for HIV infection.